Podcast – Crossing Borders: Exploring the Blood-Brain Barrier

Voice Over:

The Dementia Researcher Podcast, talking careers, research, conference highlights, and so much more.

Dr Fiona McLean:

Hello and welcome to another episode of the Dementia Researcher Podcast. This week, we’re going to be exploring the Brain’s Border Patrol and discussing the blood brain barrier, some exciting new discoveries, and its importance in the dementia research. So, let’s get going.

Hello, I’m Dr. Fiona McLean. I’m an Alzheimer’s Research UK fellow at the University of Dundee, and it’s great to be back guest hosting the show and exploring one of my favorite topics. Joining me are two amazing scientists who share my passion. I’m delighted to welcome Dr. Kate Harris from Newcastle University and Dr. Sophie Morse from the UK Dementia Research Institute at Imperial College London. Hi, both.

Dr Sophie Morse:

Hello.

Dr Kate Harris:

Hi.

Dr Fiona McLean:

So, let’s do some proper introductions. Sophie, can you tell us a little bit about yourself?

Dr Sophie Morse:

Yes, of course. So, I’m a research fellow based at Imperial College in London, and I’m split between the Department of Bioengineering and the Department of Brain Sciences where the UK Dementia Research Institute at Imperial is based. And my background, I’m a biomedical engineer, and most of my work is focused on using focused ultrasound as a way to perform therapy in the brain. And in particular, to temporarily open the blood-brain barrier so that we can get drugs into regions of the brain where we need to get them to.

Dr Fiona McLean:

That’s so cool. So, for your undergraduate degrees, did you come from the engineering route, or was it biology, or was it an actual focused degree that was bioengineering?

Dr Sophie Morse:

Yeah, it was focused degree in biomedical engineering. Yes, it was at the very beginning of when they introduced them into the country, and it was a bit of a test.

Dr Fiona McLean:

Oh, it’s worked out. It sounds really, really cool. And Kate, would you like to introduce yourself?

Dr Kate Harris:

Okay, yeah. So, I am a research fellow up at Newcastle University. And similar to Sophie, I’m kind of split between two fields. So, I have labs in the chemistry department and in the medical school, doing chemistry and then cellular neuroscience. And I guess our thing is about trying to improve translation in neurodegenerative disease drug discovery. So, finding new targets or drugging current targets better, or even just looking at different cell types. We’re particularly interested in inflammation, at the moment.

Dr Fiona McLean:

Thank you so much. It’s great to have you both join me today. For those of you who have listened to the show before, you’ll know exactly why I’m so excited to be hosting this one. And this is because this area of research is also what I work in. And just to give a little bit of background on myself, I work on the blood-brain barrier as well. And historically, I’ve been doing a lot of work to understand how obesity and type 2 diabetes can change the blood-brain barrier and cause breakdown and dysfunction, with a particular focus on what changes in transport mechanisms.

And currently, with my Alzheimer’s Research UK fellowship, I’m building on that work to better understand how amyloid buildup in the blood-brain barrier can affect it, and also then investigate the links with altered metabolic status. So, it’s so great to have three people who work on the blood-brain barrier. As I said, it’s one of my favorite things. So, let’s dig into your research a little bit more. So, Kate, can you give us a one-on-one on the blood-brain barrier and why it’s important?

Dr Kate Harris:

I can try. I think the main thing about the blood-brain barrier is it’s currently the bane of my life because I keep trying to get drugs through it. No, it’s a really important thing and it’s basically, I never really know exactly how to describe it without saying the word “barrier”, which seems a bit lame. But basically, the blood vessels surrounding your brain have a really, really thick, tightly wedged-together layer of cells that stop most things getting through unless they are specifically permitted. I am sure Sophie can do much better than that.

Dr Sophie Morse:

No, no, no, that was great. It’s a barrier.

Dr Kate Harris:

It’s a barrier, clues in the name.

Dr Fiona McLean:

I always like to think of it, I use the analogy a lot of it’s like a bouncer on a nightclub door, and it lets the good things in, kicks the trash out.

Dr Sophie Morse:

I like that.

Dr Fiona McLean:

That the way I always [inaudible 00:05:10].

Dr Kate Harris:

I think they’re more like cling film.

Dr Fiona McLean:

Oh. Any other kitchen goods that you can compare it to? It’s not quite tinfoil.

Dr Kate Harris:

Oh, no, no.

Dr Fiona McLean:

No, no. Sophie, how do you think of the blood-brain barrier when you describe it?

Dr Sophie Morse:

No, in a similar way, I suppose actually I’ve shown it in diagrams as a wall, and gaps in between the wall, and it’s like the rest of the body, the gaps are filled in with cement. Or actually, no, sorry, it’s the other way round. In the rest of the body, it’s filled in with, I don’t know, some earthy water, watery earth. I’ve got everything the wrong way around. But in the brain, it’s a lot more sort of, yeah, something not quite as tight as cement maybe, and is much of a barrier but that kind of image comes up in my mind.

Dr Fiona McLean:

Yeah, I think one of the key things is it’s super selective and there’s few places in the body that have a similar kind of barrier. The two that I can think of are the eye, the retina, which is interesting because it’s also thought of as a central nervous system component. So yeah, the blood-retina barrier is probably the other thing that’s similar. And then the other barrier that is kind of comparable and how selective it is, is the placenta.

So, I’ve actually been speaking to researchers who work on the eye and the placenta a bit more and trying to understand how these barriers have similarities but also differences, but I love the barrier. I just think it’s so cool at how it can be so selective and let certain things in, but also manage to keep certain things out and how it’s not just to do with the size of the things that we’re trying to get over or out, it’s also to do with just properties of those molecules.

Dr Kate Harris:

Can we quiz the podcast host?

Dr Fiona McLean:

Me?

Dr Kate Harris:

Yes.

Dr Sophie Morse:

Of course, you can.

Dr Fiona McLean:

Oh, that’s not how this is meant to go.

Dr Kate Harris:

We’re turning the tables on you. I just really want to know what happens on a high-fat diet to the blood-brain barrier.

Dr Fiona McLean:

All right. See, I need to get my paper out. So, I’ve worked with two mouse models previously, one which is a high fat diet mouse, and I also worked with a mouse which is known as the db./db. mouse. So, the high-fat diet mouse gets obese and mildly hyperglycemic, mildly, just a little bit above it. So, it’s almost like a pre-diabetic model, and then the db./db. mouse is a leptin receptor mutation, and so it doesn’t have proper leptin signaling. And for those of you who don’t know what leptin is about, it is basically known as the hunger hormone. So, it regulates how hungry you get. So, these mice get super hungry, they get super hyperglycemic, and they get really obese as well. So, they’re more of a model of uncontrolled type 2 diabetes. And without going into too much detail, what we are seeing is, so my work in particular focuses on endothelial cells, which are the main cell that sit in the blood-brain barrier.

And if we go back to some of the analogies, there may be the bricks in the wall. And those cells we see actually not that many changes in the high-fat diet model. So, when it’s just obesity, it’s not actually too many changes, but with the db./db. mouse, so when we have obesity with hyperglycemia, there’s so many changes. And right now, I’m unpicking that, so I use a technique called single=cell sequencing to really understand the changes that are going on in not just endothelial cells, but the different types of endothelial cells, so capillary or vein or arterial.

Dr Kate Harris:

Yeah, we need to talk after this podcast, please.

Dr Fiona McLean:

Absolutely, I love talking. Yeah, I think it’s fascinating, and, yeah, we’re working to look for maybe some targets in these cells that we could maybe then try and manipulate to improve the barrier function. But it’s not me who’s getting quizzed, so I’ve got to take this back, although I love speaking about my research. But let’s go back to you guys. So, first of all, I’d like to know of how the understanding of the blood-brain barrier’s role in dementia has changed over the last few years. Sophie, what do you think?

Dr Sophie Morse:

Well, I mean essentially, we’ve gotten better imaging tools to actually visualise how leaky or not the blood-brain barrier is in various different types of dementia, and actually found out things like the plaques and the proteins that aggregate in the brain actually and the vascular problems lead to damage to the blood vessels and leakiness. And essentially, that brings more toxins into the brain that normally wouldn’t get there.

But also leads to actually, interestingly, peripheral immune cells coming into the brain and sort of lead into… Maybe Kate has more inflammation on this side, perhaps the neuroinflammation state, but sort of exasperates that neuroinflammation state to some extent as well. There’s a lot more inflammation about how the integrity of the blood brain barrier changes with dementias and also working on techniques to try and restore the blood brain barrier as well.

Dr Fiona McLean:

Fantastic. And Kate, what do you think sort of changed in the last five, 10 years in the blood brain barrier field?

Dr Kate Harris:

Oh, gosh, that’s a question, isn’t it? Which Sophie’s answered beautifully. I think the thing that stands out most, I guess for me, is it’s probably going to be different for every neurodegenerative disease. So obviously, what Sophie were saying about peripheral immune cells getting in, that’s a classic issue with multiple sclerosis.

Maybe in other situations, that degradation is slower or happens after actually the disease-causing pathology is already undertaken. So, we really don’t understand, I don’t think, as much in things like Alzheimer’s disease or frontotemporal dementia, or I guess maybe some of the lesser well characterised ones where they’re very common, but we’re still like, “What on earth is going on pathologically in these diseases?” So, I still haven’t decided if it’s a good or a bad thing in general, probably both. Certainly, in terms of drug discovery, it can be a real pain.

Dr Fiona McLean:

Yeah, well, we’ll maybe come back to it later, but we were having a bit of a discussion before the recording started about is it a good or bad thing that you can open the blood brain barrier? But we’ll maybe come onto that in a little bit.

Dr Kate Harris:

It’s going to be a good debate.

Dr Fiona McLean:

But before we get onto that, I think Kate, you might have something to say on this, because you said the blood brain barrier is the bane of your life. So, what are some of the biggest challenges that you face when studying the blood brain barrier in relation to dementia research?

Dr Kate Harris:

So, I guess from a drug discovery perspective, it can be quite challenging to design drugs that are going to get into the brain. Now, it is not impossible, not by any means, and I probably hyped up the bane of my life a little bit, but the number of times that we’ve got really excited about a potential drug and then we’ve looked at it and gone, “Oh,” no, that’s not getting in. Oh, no.”

And the thing is, I don’t know how much you guys know about properties and drug discovery, but actually we live by a set of guidelines pretty much, but those guidelines are based on what people have observed in the past rather than actually…. So, it’s this amazing set of rules called Lipinski’s rules, where a group of people actually sat down and went, “Every drug that’s ever been dosed orally up to this point, what were their properties?” And it’s the guidelines to follow, but there’s always a subset that completely defy the laws of that and get in, so you never quite know.

Dr Fiona McLean:

That’s interesting.

Dr Kate Harris:

And the rules are more stringent for blood-brain barrier penetrance.

Dr Fiona McLean:

Actually, one of the main things on the project that I worked on with the diabetes work was they didn’t just want to know what was changing in a whole range of models, actually. It was a big European grant, so there were different people looking at different diseases, but they didn’t want to know just what was changing. They actually wanted to know what wasn’t changing because sometimes they were getting, like I say, sometimes “they”, as in the drug company people, because we had a lot of drug partners, they were finding that they were getting drugs through clinical research that were looking really good.

They even got them into healthy individuals, they saw that they were getting into the brain, but then when they moved them into people who had neurodegenerative diseases, suddenly they weren’t getting in the brain anymore. So, a lot of our research was actually looking for transporters that were preserved in these different diseases. so that you could still use the transporters to get stuff into the brain.

Dr Kate Harris:

That’s so clever.

Dr Fiona McLean:

Because I think a lot of misconception around blood-brain barrier breakdown is that breakdown means that it becomes easier to get things into the brain, which isn’t incorrect, but actually, what also happens is there’s a change in transporters. So sometimes you get an increased internalisation of a transporter, for example, and then you can no longer get something that uses that transporter into the brain anymore, even if you also do have some physical breakdown of that barrier. So, it’s hugely complex and I can see Sophie nodding away, so I’d love to hear your thoughts.

Dr Sophie Morse:

No, I’d say the biggest challenge is the complexity of it all, right? Because you don’t just study one cell type and one specific transporter. So, there’s so many different layers to the barrier itself. And then I think the other complex thing about it is, especially when using a technology like mine, where potentially you could use it for different diseases or different states, but every disease has got a different level of permeability of the blood-barrier. And depending on the stage of the disease, it’s different. And so, you might be answering one question which might apply to that specific scenario, but then it doesn’t apply to others. And so, it’s all of that and really takes a long time to figure things out. Yeah.

Dr Fiona McLean:

Absolutely. I think you’ve both took a great picture of why it is so complex and it’s such a complex entity to study as well. So just before we move on, just for our listeners who aren’t familiar with the blood beam barrier, could you both maybe describe how the blood beam barrier can change with age versus how it changes in diseases such as Alzheimer’s disease?

Dr Sophie Morse:

I can try to answer. Well, I mean, we’ve talked about the permeability increasing, which it’s not as simple as just permeability increasing, but essentially there is just more contact between what’s inside of the brain and what’s inside of the blood. And so, there’s more contact between that. And I suppose that really can lead to lots of different things. One is that toxic substances are getting in, and so they might be affecting neuronal function and lead to neuronal impairment.

But as Fiona was saying earlier, the tricky thing is that it’s not just things going in and this concept of leakiness, it’s that the actual cells that normally transport things across don’t do that necessarily in the same way as before. So, as you age, even nutrients like glucose and oxygen just have a lot harder time getting transported across and they’re just not going through as efficiently. And so, you can even get sort of hypoxic regions and that kind of thing. And the other thing I’d mention is that drug efflux pumps like glycoprotein are just not expressed as higher concentrations, and that’s also changing with age, and I think more so with dementia. So, I guess those are the main things changing with age.

Dr Fiona McLean:

I got really excited when you mentioned glucose.

Dr Kate Harris:

That’s so important. We need to talk metabolism.

Dr Fiona McLean:

Because, oh, my goodness. Yes, I’m so happy to find some metabolism fans.

Dr Kate Harris:

Can I be a loser, and please just share one thing that my most amazing students shared with me in the lab yesterday?

Dr Fiona McLean:

Absolutely. Oh, hot, hot, hot [inaudible 00:18:04].

Dr Kate Harris:

I mean, give me time. I mean, all I got was… Because we’re obviously discoveries, but we saw, we were putting microglia, the treatment is actually sulfatide, the thing that makes up myelin sheaths. and looking for mitochondrial reactive oxygen species. And we saw the mitochondria making these little, teeny tunnels and shifting the microglia, shifting their mitochondria through. And we were like [inaudible 00:18:29]-

Dr Sophie Morse:

Wait, shifting from one mitochondrion to another, or…?

Dr Kate Harris:

From microglia to another, yeah, and there were these little dots in the-

Dr Sophie Morse:

Oh, that’s super exciting.

Dr Fiona McLean:

So, they were shuttling the mitochondria between the microglia?

Dr Kate Harris:

Yeah, only the sulfatide, not with fats like lipopolysaccharides or other things. It was just with sulfatide, and I was like, “Hmm.”

Dr Fiona McLean:

What’s it up to? Wow, that’s really cool.

Dr Kate Harris:

Just wanted to share that [inaudible 00:18:55].

Dr Sophie Morse:

They’re amazing cells.

Dr Fiona McLean:

Oh, I love that. I love that. Literally, breakthroughs. You’ve heard when Kate wins a Nobel Prize, you heard it here first.

Dr Kate Harris:

[inaudible 00:19:04] the beautiful Zoe Catchpole for making these images, an amazing student, because I obviously didn’t do it.

Dr Fiona McLean:

Oh, shout out to the students. They never get an off-shout outs.

Dr Kate Harris:

So, shout out to Zoe. You’re fabulous. Thank you.

Dr Fiona McLean:

I would also like to put a shout out to, she’s now a postdoc, but my postdoc, Heather, who brought me a hot chocolate morning. Now, maybe less important from scientific breakthrough-

Dr Sophie Morse:

Special people.

Dr Fiona McLean:

… but very important to me.

Dr Kate Harris:

No, no. That is all that matters, this is what research culture is about.

Dr Fiona McLean:

Absolutely. Absolutely. So back to the blood brain barrier.

Dr Kate Harris:

Sorry.

Dr Fiona McLean:

No, no. I love a side thing, but that is so exciting. And so, I feel that one thing we haven’t discussed yet actually is the different cell types in the blood-brain barrier. So, I previously mentioned endothelial cells, so they make up sort of the main part of the vessel. So, the blood-brain barrier sits in the blood micro vessels in the brain. And so, what am I doing here? You can’t see this because it’s a podcast, but if you’re watching the video version, I’m making a circle with my hand.

Dr Kate Harris:

That’s beautiful.

Dr Fiona McLean:

Thank you. And this is where the endothelial cells sit. They make up this kind of circle, but then they have pals that help them out. So, then they also have other cell types. So, they have pericytes, which they’re kind of… How would you describe a pericyte? So, everyone I work with is obsessed, as in who I collaborate with, is obsessed with pericytes. And I like pericytes, but I just can’t love them as much as I love the endothelial cell. So, I’m going to leave this to… Sophie’s smiling. Okay, tell us about a pericyte.

Dr Sophie Morse:

Well, I think the key thing about pericytes is they kind of wrap around the endothelial cells and they’re involved in changing the size of the blood vessels, the sort of constriction and opening of them. And yeah, they actually cover most of the endothelial cells in some cases, don’t they?

Dr Fiona McLean:

Yeah. I don’t want to get in trouble, but I always think of them as a sort of type of smooth muscle cell.

Dr Sophie Morse:

Yes, I do too, actually.

Dr Fiona McLean:

But then sometimes, you speak to some people who love a pericyte and they just [inaudible 00:21:09].

Dr Sophie Morse:

They don’t like that.

Dr Fiona McLean:

They look at you, just really disappointed. They’re just like, “Oh…”

Dr Kate Harris:

What do they want it to be?

Dr Fiona McLean:

Well, they are special, aren’t they? [inaudible 00:21:17]-

Dr Sophie Morse:

Yeah, I suppose they’re so much smaller than muscle.

Dr Kate Harris:

[inaudible 00:21:18].

Dr Fiona McLean:

Yeah, and if you knock out pericytes, like if you get rid of them, big issues. But as I said to one researcher who loves pericytes, I was like, “It doesn’t kill the thing. You can survive without pericytes.”

Dr Kate Harris:

Is this your definition of special? “You can’t live without it.”

Dr Fiona McLean:

Maybe. I was like, “But you can’t survive without the endothelial cells, so…”

Dr Kate Harris:

Maybe every one’s equally important.

Dr Fiona McLean:

I think so. So anyway, we have the endothelial cells, which make up the main part of the vessel. We have the pericytes, which wrap around. We have smooth muscle vascular cells, which are to do with the constriction of vessels. And then I can see Kate, I feel like because she’s already mentioned them, we have… Well, I was going to mention microglia. They don’t really attach to the vessels, but they’re in there. They’re in the mix. They’re at the party. But we also have to mention the astrocytes. So, the astrocytes, which are cells which have these lovely long feet, their feet stick on to the vessels as well. And I actually think astrocytes are quite cool. They do a lot of exchange of nutrients and other things with endothelial cells. And Kate’s nodding. So, tell us about astrocytes and the blood brain barrier.

Dr Kate Harris:

I actually have a confession to make, in that I think I am one of those astrocyte ignorers, and I want to apologise to astrocytes, because they often get overlooked. I don’t know whether you guys agree, but it’s often neurons, microglia, and obviously microglia, beautiful, neurons beautiful. But I just feel like poor, poor astrocytes, like when we used to do our neurogenesis experiments, we would stain up for astrocytes just so that we knew they were there. We didn’t really care. But actually, they’re really important structurally, and they play a huge, huge role in supporting the overall, I call it skeleton, but probably not the correct word. And making that really crucial link. Pretty much wherever a neuron, or microglia, or an oligodendrocyte is doing something cool that will be an astrocyte there being like, “I got your thumb, I’ll hold you.”

Dr Fiona McLean:

I love that. They’re like the support network. They’re like, “I got you.”

Dr Kate Harris:

They are, they’re like your rock.

Dr Fiona McLean:

See, I don’t think they are overlooked at the moment, but I think that’s because there’s some really fabulous astrocyte work done at Edinburgh University in the Dementia Research Institute there-

Dr Sophie Morse:

Oh, nice.

Dr Fiona McLean:

… by, I know Blanca does a lot of work there. They do some lovely work with astrocytes. So, I feel like there is people who are rooting for the astrocytes out there. So don’t worry, Kate.

Dr Kate Harris:

Okay, that makes me feel better there.

Dr Fiona McLean:

There are people there. Yep, don’t worry. But yeah, they’re great. They are great.

Dr Kate Harris:

I just want of the astrocytes to know that I do think they make a valuable contribution.

Dr Fiona McLean:

Well, now they know, it’s on a podcast. So now that we understand a little bit more about the structure of the blood-brain barrier and the different cell types, and the roles that they play, let’s move on a little bit more to your work in depth. So, let’s start with Sophie. So, you’ve had a recent publication in Nature. Congratulations, you’ve made it, you can now retire. That’s it. Pinnacle, done, Nature published.

Dr Kate Harris:

Child prodigy.

Dr Fiona McLean:

Child prodigy. So, I would love to hear more about that. So, your paper is around microbubbles, so tell us more.

Dr Sophie Morse:

Yes, yeah, so I’ll describe how it works. Basically, the ultrasound, instead of using it normally and safely as it’s… Well, it is safe, but I’m just saying that instead of using it normally to sort of scan for babies or the inside of your body, basically you can use a safe technology in a completely different way, which involves focusing the ultrasound waves onto a specific target. And what that means is that you can focus that target onto anywhere you want, and it can be small or larger. And in the brain, if you focus it onto even really deep reach into the brain, you can essentially get anywhere in the brain you want with the ultrasound, if you inject the drug that you want to deliver across the blood-brain barrier and these tiny, tiny bubbles that’ve got a lipid or protein shell and a [inaudible 00:25:48] core, what happens is that the bubbles and the drug are everywhere in the body, but only where you focus the ultrasound onto a specific region of the brain will the bubbles oscillate.

And so, they gently oscillate inside of the blood vessels. And what they do is they create mechanical forces on the endothelial cells and basically open up the blood brain barrier. And this is super cool, essentially because all the drugs, the novel drugs that you’re making or the old drugs that haven’t worked because they haven’t gotten through the blood brain barrier, you could use this technology in a non-invasive way to open the barrier. And it’s temporary. The barrier opens and then it closes up afterwards. So, it’s kind of a non-invasive way of doing this. And the publication that came out earlier this year, a lot of it was done by my student, William Lee-Ki Chan.

Dr Fiona McLean:

Shout out to student again.

Dr Sophie Morse:

Yes, shout out to William. His work is really showing that you can get all sorts of different sizes of drugs across into the brain, really, really small ones, much larger proteins, antibodies, all the way to drug carriers like liposomes and nanoparticles. So that was the key to that publication.

Dr Kate Harris:

Sorry, I know my mouth is wide open, but this is [inaudible 00:27:08].

Dr Fiona McLean:

It’s so cool.

Dr Kate Harris:

Oh, my goodness.

Dr Fiona McLean:

But I have two questions. One question for me is how specific are we talking when you say you can open the blood-brain barrier in a specific region? Are we talking microns? Are we talking like a region of the brain?

Dr Sophie Morse:

Yes, it depends on the frequency of the ultrasound that you use. In our experiments, we tend to open an area of about one times two millimeters, but it can be much larger. We can cover the whole left hemisphere of, say, a mouse sprain, for example, but it either really depends on the transducer that you’re using, but in the order of millimeters, and then you could move the target and focus a much larger area if you move it.

Dr Fiona McLean:

Great. And when the barrier opens, is it almost anything could get through, or is it specific to what the drugs that you’ve sort of putting in, or-

Dr Sophie Morse:

Yeah, it’s a mixture, because really what’s happening is you are getting gaps in between the cells. So, the tight junctions are opening, and depending on how much you’re opening that, different sizes we’ll be able to get through. But you’ll also getting increased transport through the cells themselves, and there’s drug reflux pumps that are sort of toned down temporarily. So, it’s kind of three different things happening. And so, no, it’s true that with some, depending on how much pressure you are putting in with the ultrasound waves, you can get much larger open and much smaller. So sometimes, we’ll do an opening where only up to a certain size molecule will get across and not beyond that. So size is a big factor.

Dr Fiona McLean:

So recently, we’ve heard about novel treatments, which are for the removal of amyloid from the brain. And what I was wondering, with your technique, could you also maybe apply it, and if you’re creating these openings in the blood-brain barrier, could then we remove stuff like amyloid from the brain?

Dr Sophie Morse:

Well, that’s very, very interesting, and it’s part of the research that my grief is doing at the moment, actually, because there are two things that can happen here. One, you’re right, you’re opening the barrier so you can get stuff coming out. My gut feeling is that you wouldn’t be able to get everything to come out, so any things nearby. And that’s super cool because you could use it as a liquid biopsy. You could take a blood sample after opening the barrier to be able to detect wherever someone’s got, say, a certain type of disease, different stage, or something like that. So that’s super cool direction of that research.

But what’s interesting is that if you open the barrier, stuff goes in, not only your drug, but other blood-derived proteins, etc. What that does is it elicits an activation of the microglia and the astrocytes. So, they get sort of alerted, “Oh, there’s something here, we need to clear it up.” And actually, what happens is that not only do they clear out this stuff that’s moved into the brain, but also, they start clearing the amyloid. So that’s what’s really cool in the very recent research we’re doing, is that even if you just open the barrier without delivering a drug, the microbe will be activating and trying to clear out more of the plaques. So, it’s almost like an alert in the brain of something.

Dr Fiona McLean:

It’s almost like a kickstart.

Dr Sophie Morse:

Yes, yes, exactly.

Dr Fiona McLean:

It’s like telling the brain… Yeah, it’s almost, if the brain has almost become habituated to maybe a disease status-

Dr Sophie Morse:

Yeah, it’s ignoring it.

Dr Fiona McLean:

Yeah, it’s ignoring it because it’s become the norm in the brain. But then if you shove something else and it goes, “Whoop.”

Dr Sophie Morse:

Yeah, wake it up.

Dr Fiona McLean:

Wake it up, and it’s like, “Actually, I need to be doing something here.” That’s really, I love this stuff. It’s so, so interesting. You see, Kate is also loving this stuff.

Dr Kate Harris:

I’m in love. I’m just thinking, can you imagine, right if you did your little liquid brain biopsy… I say “little”, it’s amazing. It’s groundbreaking. Apologies. I don’t mean little like that.

Dr Sophie Morse:

No, no, don’t worry.

Dr Kate Harris:

Because I don’t know about you, but are you guys ever involved in the big versus little soluble amyloid toxicity debate? So, I’m wondering if you could look at what’s released and go, “Well, in the patients that are declining much faster, does that liquid biopsy contain more or less soluble versus complete amyloid?” Because obviously, well people who don’t have any disease pathology also have brains riddled with amyloid in old age. So, we could actually start understanding, “What on Earth is going on?” In my head, that’s the first question.

Dr Fiona McLean:

It’s really cool.

Dr Sophie Morse:

So exciting.

Dr Kate Harris:

I’m just like, “What? What?”

Dr Fiona McLean:

I think, so what I was going to ask Sophie is how translatable is this to humans? I know at Dundee we got a new-

Dr Sophie Morse:

I know, super exciting.

Dr Fiona McLean:

Sorry, it’s a new MRI ultrasound machine here, and there was some really fabulous fundraising to get it. I think there’s only two in the UK, or there’s maybe three now. And a lot of the work at Dundee is actually being focused on tremors, and doing focused ultrasound to alleviate these tremors, which it is a different story, maybe not for today, but if you’re out there, you should look it up. It’s just fantastic.

Dr Sophie Morse:

Oh, it’s amazing. It’s like magic.

Dr Fiona McLean:

It is. So, is that the type of machine that you could use?

Dr Sophie Morse:

Yes, it’s exactly the same one. You just add the bubbles, the microbubbles, and the drug injection.

Dr Kate Harris:

Bubbles, words for life.

Dr Fiona McLean:

Maybe I need to do some introductions with Sophie and the researchers, the clinical researchers at Dundee, because yeah, if we can translate this stuff into humans, it’d be so exciting.

Dr Sophie Morse:

I know, I know.

Dr Kate Harris:

And then maybe one day you can develop a little device that you just put on for an hour after you’ve taken your drug.

Dr Sophie Morse:

That is the dream.

Dr Kate Harris:

Can you imagine, just put on some headphones?

Dr Fiona McLean:

Just around your head.

Dr Sophie Morse:

Portable.

Dr Fiona McLean:

Or like a sweatband.

Dr Kate Harris:

Sweatband.

Dr Fiona McLean:

And then it gives you the pulses.

Dr Kate Harris:

And you’re like, “You take this just before a meal, so you’ve not got too much sugar to go into your brain whilst doing exercise. You increase neurogenesis after having your compound. Just let’s rule everybody’s lives.”

Dr Sophie Morse:

Protocol.

Dr Fiona McLean:

Sophie, I feel like we could talk about your research forever, but I also really want to hear about Kate’s research.

Dr Kate Harris:

Do we, though?

Dr Sophie Morse:

Yes, we do.

Dr Fiona McLean:

Yes, of course. So, Kate, you’re working on drug targets. Tell us about it.

Dr Kate Harris:

Yes. Oh, goodness gracious. After Sophie, I don’t know what to say.

Dr Sophie Morse:

No, you’re making the amazing drugs.

Dr Kate Harris:

Well, they are not amazing yet. I’d love them to be amazing.

Dr Fiona McLean:

Yet, yet. So then this is why we have collaboration.

Dr Kate Harris:

Exactly.

Dr Fiona McLean:

Kate, you make the drugs, Sophie, you get them in [inaudible 00:33:58].

Dr Sophie Morse:

Yeah, I’ll get them across.

Dr Kate Harris:

We could do this. We could do this. My life just got a whole lot easier. Thank you.

Dr Fiona McLean:

But Kate, tell us about it. What are you up to?

Dr Kate Harris:

Yeah, so I guess maybe the thing maybe most important for this podcast is actually our ethos of interdisciplinary working. So, drug discovery is classically when you’re making the drugs, it’s classically a chemistry thing. You have to design and make them if you’re working on chemical drugs and not biologics. But one of the things that we’re missing in one neurodegenerative disease research is actually that translation. It’s come up so many times today already, this comes along and then we don’t translate, or this comes along and then we don’t have the machine to translate it to humans or whatever. And one of the big early challenges is that translation between a disease hypothesis and then the ability to drug it.

Once you’ve got your hypothesis, there’s a whole world of work that has to then go into validating that, particularly in cell-based assays. And the reason I mention this is because the classical way of doing drug discovery is by picking one target and going, “We’re going to make a drug for that.” And then in a certain cancer and in monogenic diseases, that works really well, but we don’t even know what’s going on biologically well enough yet in neurodegenerative diseases to do that. So, what we actually need is to look at the cellular change for now, and maybe hit multiple targets at a time. So that’s what we work in. We work in understanding the molecular mechanisms behind the disease and then trying to work out if it’s druggable.

Dr Fiona McLean:

Fantastic, yeah.

Dr Kate Harris:

We need collaborations with people right up and down the chain because that’s the only way this is going to work.

Dr Sophie Morse:

Yeah.

Dr Fiona McLean:

Absolutely. Yeah, I think it’s really exciting to talk to both of you because I love treatment-focused research. I think we really need to push in the UK towards treatments. And I think that’s where even though the new treatments that have come out for dementia aren’t perfect, I think it’s a real signal to the governing bodies that, with proper support and research money put into this, we actually could get there and get really successful treatments, so yeah-

Dr Kate Harris:

It’s restoring confidence, isn’t it?

Dr Fiona McLean:

Absolutely, because it’s been so unsuccessful for pretty much the whole time it’s been researched, in terms of Alzheimer’s disease. I don’t want to use the word “failure” because I don’t believe it is a failure. I feel like we’ve been building up a picture for decades now of what’s going on, and I feel like we’re actually getting to the top of the mountain, where we’re starting to see the possibility of really life-changing treatments being developed, but we just need that extra push, that extra support with funding at a government level, in my opinion, because we need big money invested to really get that push there.

Dr Kate Harris:

That would be absolutely, lovely. Yes, please.

Dr Fiona McLean:

Yeah, our charities do so much for us. I mean, I mentioned I’m funded by Alzheimer’s Research UK. I would not be doing this work without them. I think yourself, Sophie, you’re funded through the Dementia Research Institute-

Dr Sophie Morse:

Yeah.

Dr Fiona McLean:

… which has a big charity-funded component.

Dr Sophie Morse:

Exactly, yeah.

Dr Fiona McLean:

And yourself, Kate.

Dr Kate Harris:

I’ve been lucky enough to get an Alzheimer’s Research UK pilot project grant, which-

Dr Sophie Morse:

Oh, that’s amazing.

Dr Fiona McLean:

Charity money, though.

Dr Kate Harris:

… wonderful. Yes, I think all my money has been charity money, apart from the wonderful fellowship that Newcastle gave me to start my group.

Dr Fiona McLean:

Fantastic. So yeah, I think big shout out to charities who-

Dr Kate Harris:

Thank you.

Dr Fiona McLean:

… fund this research and keep us going.

Dr Kate Harris:

Thank you for taking a punt on a chemist, Alzheimer’s Research UK.

Dr Fiona McLean:

Thank you for taking a punt on someone who was doing diabetes research.

Dr Kate Harris:

It’s so closely linked.

Dr Fiona McLean:

It is so closely linked. And yeah, I think for people who aren’t familiar with the links between diabetes and Alzheimer’s disease, the figure that always sticks in my mind is that if you have type 2 diabetes, you’re twice as likely to go on and develop Alzheimer’s disease.

Dr Kate Harris:

Terrifying.

Dr Fiona McLean:

So, for me, in my research, it’s understanding why that is because for me, a big fact like that, we have to understand why that is. That’s a solid bit of research. So why?

Dr Kate Harris:

Did we do another one in inflammation and discuss it?

Dr Sophie Morse:

Oh, amazing.

Dr Fiona McLean:

Listen, I’m still waiting for the diabetes [inaudible 00:38:25].

Dr Kate Harris:

Oh, yes.

Dr Fiona McLean:

So, we’re running out of time, sadly, but I’d like to just finish up on a couple of questions. So, what future developments do you both see in the field of blood-brain bioresearch and its importance in solving the problem of dementia? So where would we like to see in the next five to 10 years, this research goal? I’ll start with you, Sophie. We’ve kind of touched on some of it.

Dr Sophie Morse:

Yeah, I’d say basically getting it into patients so that it’s a clinically approved treatment, and that’s kind of starting. Clinical trials have shown that it’s safe to repeatedly do that in humans, but to actually get drugs across and show that therapeutic efficacy would be absolutely amazing, yeah.

Dr Fiona McLean:

So basically, you need to come to Dundee [inaudible 00:39:11] about the machine, got to do it. And Kate, what about yourself? Where would you like to see this?

Dr Kate Harris:

I would really like to see more collaboration between drug discovery scientists and specialists like Sophie, to work out what we can make the most of in the blood-brain barrier to get through. Because our biggest challenge is designing compounds that get through. It sounds like, with a bit of clever design, we might be able to do it easier. I want to see more collaboration.

Dr Sophie Morse:

Yes, yeah. I think that would be fantastic, yeah.

Dr Fiona McLean:

That is exciting. And just to end on, we have a lot of early-career researchers who’ve listened to this podcast. So, Sophie, what advice would you give to any of the early-career researchers listening on how to get into this field? Because you came in through a really unique way.

Dr Sophie Morse:

Yeah, so a very odd way to get into it, as an engineer. I suppose I’d say please join if you’re not joined already. Please do. Because the problem’s so complex, there’s so many challenges. The more there are of us, the better. And we really need people that have got completely different ways of working and mindsets. And really that diversity just makes everything a lot better and faster. So, I’d say, please join if you [inaudible 00:40:26].

Dr Fiona McLean:

Couldn’t agree more. People from different backgrounds, different disciplines, we need different ways of thinking to solve the big problems.

Dr Sophie Morse:

Yeah.

Dr Fiona McLean:

Couldn’t agree more. And yourself. Kate, what advice would you give to any [inaudible 00:40:36] listening?

Dr Kate Harris:

I would say follow the butterflies. And what I mean is that little feeling in your stomach you get when you’re onto something, that, hold onto that. And if something about that excites you, I mean, I actually trained as a cancer research person, but now I don’t know, I got butterflies when I thought about the brain. And then it’s really rewarding, and trust that gut, because even if you can’t articulate it yet, your subconscious has made some links and has made a scientific hypothesis. So, trust that in yourself and do what interests you.

Dr Fiona McLean:

I love that, absolutely. And my last question, so I asked this in the vascular podcast that I did a while ago, but I’ve already said my favourite blood-brain barrier cell type. Big shout out to the endothelial cells. What’s your favourite cell type in the blood-brain barrier, Sophie?

Dr Sophie Morse:

I’d be torn between microglia and astrocytes. So, I’d probably go for astrocytes because I know maybe Kate might say microglia.

Dr Fiona McLean:

You’re keeping all the cells happy. Kate, what’s your favourite blood-brain barrier?

Dr Kate Harris:

I was about to go to astrocytes to make me feel better.

Dr Sophie Morse:

Oh, no, that microglia are sad somewhere.

Dr Kate Harris:

Oh, sorry, pericytes, pericytes. [inaudible 00:41:53] jokes.

Dr Fiona McLean:

Pericytes have enough fans out there.

Dr Kate Harris:

Absolutely, microglia, astrocytes.

Dr Fiona McLean:

Pericytes remind me of that cool alternative indie band.

Dr Kate Harris:

It makes me think of periscopes.

Dr Sophie Morse:

So, submarines.

Dr Kate Harris:

Like sticking their head above the parapet being like, “Is everything okay? Do we need to open any gates?” I’m so sorry for the listeners, for myself.

Dr Sophie Morse:

Love it.

Dr Fiona McLean:

No, that’s fantastic. So, we’ve got a couple of astrocyte fans, and you were worried that nobody cared. There you go. I’m going to stick with endothelial cells because I think I’m yet to hear someone else say that.

Dr Kate Harris:

Stick to your guns, you follow those principles.

Dr Fiona McLean:

Stick to them, I love that they’re such hard workers. They’re shuttling things back and forth.

Dr Kate Harris:

Oh, yeah, they are grafters.

Dr Fiona McLean:

They are grafters, and I respect that. On that note, I think that’s all we have time for today, but if anyone listening can’t get enough of this topic, visit the Dementia Researcher website, where you’ll find a full transcript, biographies on our guests, blogs, and much more on this topic. And I would just like to take a second to thank our incredible guests, Dr. Kate Harris, and Dr. Sophie Morse. I’m Fiona McLean and you’ve been listening to the Dementia Researcher Podcast. Bye.

Dr Sophie Morse:

Bye.

Dr Kate Harris:

Bye.

Voice Over:

The Dementia Researcher Podcast was brought to you by University College London, with generous funding from the UK National Institute for Health Research, Alzheimer’s Research UK< Alzheimer’s Society, Alzheimer’s Association, and Race Against Dementia. Please subscribe, leave us a review, and register on our website for full access to all our great resources. dementiaresearcher.nihr.ac.uk.

END